2,4-pentadienoic acid derivatives having retinoid-like biological activity

ABSTRACT

Compounds of Formula 1 ##STR1## wherein Z is selected from the group consisting of the radicals shown in Formula 2 and in Formula 3, ##STR2## Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substituted with one or two R 4  groups, or Y is selected from phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 4  groups, the divalent Y radical being substituted by the Z and --CR 1  ═CR 1  --CR 1  ═CR 1  groups on adjacent carbons; X is S, O, or NR 5  ; n is 1 or 2; R 1  and R 2  independently are H, lower alkyl or fluoroalkyl; R 3  is hydrogen, lower alkyl, Cl or Br; R 4  is lower alkyl, fluoroalkyl or halogen; R 5  is H or lower alkyl, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9  R 10 , --CH 2  OH, CH 2  OR 11 , CH 2  OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13  O, --COR 7 , CR 7  (OR 12 ) 2 , CR 7  OR 13  O, or tri-lower alkylsilyl, where R 7  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8  is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons, have retinoid like biological activity.

1. Field of the Invention

The present invention relates to novel compounds having retinoid-likeactivity. More specifically, the present invention relates to compoundshaving a 2,4-pentadienoic acid or 2,4-pentadienoic acid ester functionwhich is substituted in the 5-position with a tetrahydronaphthyl-aryl,chromanyl-aryl, thiochromanylaryl, 1,2,3,4-tetrahydroquinolinyl-aryl orwith a tetrahydronaphthyl-cycloalkyl, chromanyl-cycloalkyl,thiochromanyl-cycloalkyl, 1,2,3,4-tetrahydroquinolinylcycloalkyl group.The acid function may also be converted to an alcohol, aldehyde orketone or derivatives thereof, or may be reduced to --CH₃, and thetetrahydronaphthyl-aryl, chromanyl-aryl, thiochromanylaryl,1,2,3,4-tetrahydroquinolinyl-aryl, tetrahydronaphthyl-cycloalkyl,chromanyl-cycloalkyl, thiochromanyl-cycloalkyl, and1,2,3,4-tetrahydroquinolinyl-cycloalkyl groups may be furthersubstituted with one or more alkyl substituents.

2. Background Art

Compounds which have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory ache, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil®, diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

U.S. Pat. Nos. 4,740,519 (Shroot et al.), 4,826,969 (Maignan et al.),4,326,055 (Loeliger et al.), 5,130,335 (Chandraratna et a.1,), 5,037,825(Klaus et al.), 5,231,113 (Chandraratna et al.), 5,324,840(Chandraratna), Published European Patent Application Nos. 0 176 034 A(Wuest et al.), 0 350 846 A (Klaus et.al.), 0 176 032 A (Frickel etal.), 0 176 033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 0 303915 A (Bryce et al.), UK Patent Application GB 2190378 A (Klaus et al.),German Patent Application Nos. DE 3715955 A1 (Klaus et al.), DE 3602473A1 (Wuest et al., and the articles J. Amer. Acad. Derm. 15:756-764(1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo etal.), J. Med Chem. 1988 31, 2182-2192 (Kaqechika et al.), Chemistry andBiology of Synthetic Retinoids CRC Press Inc. 1990 p 334-335, 354(Dawson et al.), describe or relate to compounds which include atetrahydronaphthyl moiety and have retinoid-like or related biologicalactivity.

U.S. Pat. Nos. 5,278,318, 5,324,840, 5,324,744, 5,346,895, 5,346,915,5,348,972, 5,348,975, 5,354,752 assigned to the assignee of the presentapplication, describe or relate to compounds which include a chromanyl,thiochromanyl, or 1,2,3,4-tetrahydroquinolinyl moiety and haveretinoid-like or related biological activity.

U.S. Pat. No. 5,344,959 describes cyclopropyl substituted 1,3-butadienederivatives having retinoid-like biological activity.

Several co-pending applications and recently issued patents which areassigned to the assignee of the present application, are directed tofurther compounds having retinoid-like biological activity.

SUMMARY OF THE INVENTION

The present invention covers compounds of Formula ##STR3##

wherein Z is selected from the radicals shown in Formula 2 or in Formula3, ##STR4##

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R₄ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiazolyl, oxazolyl, and imidazolyl, said groups being optionallysubstituted with one or two R₄ groups, the divalent Y radical beingsubstituted by the Z and --CR₁ ═CR₁ --CR₁ ═CR₁ groups on adjacentcarbons;

X is S, O, or NR₅ ;

n is 1 or 2;

R₁ and R₂ independently are H, lower alkyl or fluoroalkyl;

R₃ is hydrogen, lower alkyl, Cl or Br;

R₄ is lower alkyl, fluoroalkyl or halogen;

R₅ is H or lower alkyl, and

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or tri-lower alkylsilyl, where R₇ isan alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ isan alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbonsor trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R₈is phenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen,an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl orlower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radicalof 2-5 carbons.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 for the treatment of skin-related diseases, including,without limitation, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory ache, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsare also useful for the prevention and treatment of cancerous andprecancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withHuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil®, diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 1 in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to processes for making acompound of Formula 1 which processes comprise reacting a compound ofFormula 4 with a compound of Formula 5 in the presence of strong base,or reacting a compound of Formula 4 with a compound of Formula 6 in thepresence of strong base. Alternatively, in the processes for making acompound of Formula 1, the aldehyde function of Formula 4 and thedialkylphosphonate of Formula 5, or the triphenylphosphonium bromidefunction of Formula 6, can be interchanged. In Formula 5 and Formula 6the symbol B' represents B as defined above in connection with Formula1, or such protected derivative of the group B from which the B groupcan be readily obtained by reactions well known to the practicingorganic chemist. Still further, the present invention relates to suchreactions performed on the compounds of Formula 1 which causetransformations of the B group while the reaction product still remainswithin the scope of Formula 1. ##STR5##

GENERAL EMBODIMENTS

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

Lower alkyl means the above-defined broad definition of alkyl groupshaving i to 6 carbons in case of normal lower alkyl, and as applicable 3to 6 carbons for lower branch chained and cycloalkyl groups. Loweralkenyl is defined similarly having 2 to 6 carbons for normal loweralkenyl groups, and 3 to 6 carbons for branch chained and cyclo- loweralkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6carbons for normal lower alkynyl groups, and 4 to 6 carbons for branchchained lower alkynyl groups.

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. It includes organic and inorganic esters. Where B of Formula1 is --COOH, this term covers the products derived from treatment ofthis function with alcohols or thioalcohols preferably with aliphaticalcohols having 1-6 carbons. Where the ester is derived from compoundswhere B is --CH₂ OH, this term covers compounds derived from organicacids capable of forming esters including phosphorous based and sulfurbased acids, or compounds of the formula --CH₂ OCOR₁₁ where R₁₁ is anysubstituted or unsubstituted aliphatic, aromatic, heteroaromatic oraliphatic aromatic group, preferably with 1-6 carbons in the aliphaticportions.

Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di- substituted amides. Unless statedotherwise in this application, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula-CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₇ O-- where R₇ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds inthis invention having a functionality capable of forming such-salt, forexample an acid functionality. A pharmaceutically acceptable salt is anysalt which retains the activity of the parent compound and does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may by be made with amines, particularlyammonium salts such as mono-, di- and trialkyl amines or ethanol amines.Salts may also be formed with caffeine, tromethamine and similarmolecules. Where there is a nitrogen sufficiently basic as to be capableof forming acid addition salts, such may be formed with any inorganic ororganic acids or alkylating agent such as methyl iodide. Preferred saltsare those formed with inorganic acids such as hydrochloric acid,sulfuric acid or phosphoric acid. Any of a number of simple organicacids such as mono-, di- or tri- acid may also be used.

The compounds of the present invention have trans and cis (E and Z)isomers. In addition, the compounds of the present invention may containone or more chiral centers and therefore may exist in enantiomeric anddiastereomeric forms. The scope of the present invention is intended tocover all such isomers per se, as well as mixtures of cis and transisomers, mixtures of diastereomers and racemic mixtures of enantiomers(optical isomers) as well. In the present application when no specificmention is made of the configuration (cis, trans or R or S) of acompound (or of an asymmetric carbon) then a mixture of such isomers, oreither one of the isomers is intended. In a similar vein, when in thechemical structural formulas of this application a straight linerepresenting a valence bond is drawn to an asymmetric carbon, thenisomers of both R and S configuration, as well as their mixtures areintended. A straight horizontal single line or a wavy single line drawnto a carbon with a double bond denotes either cis or trans or bothorientations of the substituent on the double bond. Specific orientationof substituents relative to a double bond is indicated in the name ofthe respective compound, and/or by specifically showing in thestructural formula the orientation of the substituents relative to thedouble bond.

With reference to the symbol Y in Formula 1, the preferred compounds ofthe invention are those where Y is cyclopropyl, phenyl, pyridyl,thienyl, or furyl. Even more preferred are compounds where Y iscyclopropyl or phenyl. In the preferred compounds of the invention thereis no optional R₄ substituent on the Y group.

The R₁ substituent of the preferred compounds of the invention ispreferably H or methyl. The B substituent of the preferred compounds isCOOH or a pharmaceutically acceptable salt thereof, or COOR₈ or CONR₉R₁₀ where R₈, R₉ and R₁₀ are as defined above. Even more preferably R₈,R₉ and R₁₀ are lower alkyl.

Referring now to the radical symbolized by Z in Formula 1, it ispreferably 5,6,7,8-tetrahydronaphthyl (Formula 2 where n is 2),chromanyl or thiochromanyl (Formula 3 where X is S or O). The Y group ispreferably attached to the tetrahydronaphthalene group in the 2 or 3position, and to the chroman or thiochroman ring in the 6 or 7 position.The R₃ substituent is preferably H or lower alkyl. Even more preferablythe R₃ group is H or methyl, the Y group is attached to thetetrahydronaphthalene ring in the 2 position and to the chroman orthiochroman ring in the 6-position. The R₂ group is preferably H ormethyl.

Specific preferred compounds in accordance with Formula 1 and theirsynthesis are described below in the section of this application titled"Specific Examples". The presently most preferred compounds of theinvention in accordance with Formula 1 are indicated in Table i below,with reference to Formula 7, Formula 8 and Formula 9. The numbering ofthe pentadienoic acid chain of these compounds is indicated in Formula7. In the preferred compounds of the invention the ▴⁴ double bond istrans. ##STR6##

                  TABLE 1                                                         ______________________________________                                                                         Config-                                                                             Config-                                                                             Config-                                                           uration                                                                             uration                                                                             uration                                                           about about about                            Compound                         cyclo-                                                                              Δ.sup.2                                                                       Δ.sup.4                    Number  Formula  X     R.sub.3                                                                            R'.sub.8                                                                           propane                                                                             bond  bond                             ______________________________________                                        1       7        --    H    Et   cis   trans trans                            2       7        --    H    H    cis   trans trans                            3       7        --    H    Et   trans cis   trans                            4       7        --    H    Et   trans trans trans                            5       7        --    H    H    trans cis   trans                            6       7        --    H    H    trans trans trans                            7       8        --    H    Et   --    trans trans                            8       8        --    H    Et   --    cis   trans                            9       8        --    H    H    --    trans trans                            10      8        --    H    H    --    cis   trans                            11      7        --    CH.sub.3                                                                           Et   cis   trans trans                            12      7        --    CH.sub.3                                                                           Et   cis   cis   trans                            13      7        --    CH.sub.3                                                                           H    cis   trans trans                            14      7        --    CH.sub.3                                                                           H    cis   cis   trans                            15      9        S     H    Et   cis   trans trans                            16      9        S     H    Et   cis   cis   trans                            17      9        S     H    H    cis   trans trans                            18      9        S     H    H    cis   cis   trans                            19      9        O     H    Et   cis   trans trans                            20      9        O     H    Et   cis   cis   trans                            21      9        O     H    H    cis   trans trans                            ______________________________________                                    

Modes of Administration

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic ache or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards it expansion. In certain instances, the compoundpotentially may be used in prophylactic manner to prevent onset of aparticular condition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per mililiter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many disease for which thesecompounds are useful.

Assay of Retinoid-like Biological Activity

The retinoid-like activity of the compounds of the invention can beconfirmed in assays wherein ability of the compound to modulateprocesses mediated by retinoid receptors, and ability of the compoundsto bind to retinoid receptors is measured. It is now general knowledgein the art that two main types of retinoic acid receptors exists inmammals (and other organisms). The two main types or families arerespectively designated RAR and RXR receptors. Within each type thereare sub-types, designated RAR.sub.α, RAR.sub.β, RAR₆₄ , RXR.sub.α,RXR.sub.β and RXR.sub.Γ. It has also been established in the art thatthe distribution of the two main retinoid receptor types, and of theseveral sub-types is not uniform in the various tissues and organs ofmammalian organisms. Moreover, specific or selective agonist-likeactivity on RXR receptors, in preference over RAR receptors tends toresult in certain beneficial retinoid-like properties while avoidingcertain undesirable side effects. Similarly, selective agonist likeactivity of only one or two retinoid receptor subtypes within oneretinoid receptor family can also give rise to beneficialpharmacological properties because of the varying distribution of thesub-types in the several mammalian tissues or organs. For theabove-summarized reasons, agonist-like activity in any or all of theretinoid receptors, as well as specific or selective activity in the RXRreceptor family, or selective or specific activity in any one of thereceptor subtypes, are all considered desirable pharmacologicalproperties.

In light of the foregoing the prior art has developed assay proceduresfor testing the agonist like activity of compounds in the RAR.sub.α,RAR.sub.β, RAR.sub.Γ, RXR.sub.α, RXR.sub.β and RXR.sub.Γ receptorsubtypes. For example, a chimerio receptor transactivation assay whichtests for agonist-like activity in the RAR.sub.α, RAR.sub.β, RAR.sub.Γ,RXR.sub.α receptor subtypes, and which is based on work published byFeigner P. L. and Holm M. (1989) Focus, 11 2 is described in detail inpublished PCT Application No. WO WO94/17796, published on Aug. 18, 1994.The latter publication is the PCT counterpart of U.S. application Ser.No. 08/016,404, filed on Feb. 11, 1993, in which a Notice of Allowancehas been issued. PCT publication WO94/17796 and the specification ofU.S. application Ser. No. 08/016,404 are hereby expressly incorporatedby reference.

A holoreceptor transactivation assay and a ligand binding assay whichmeasure the agonist like activity of the compounds of the invention, ortheir ability to bind to the several retinoid receptor sub-types,respectively, are described in published PCT Application No. WOW093/11755 (particularly on pages 30-33 and 37-41) published on Jun. 24,1993, the specification of which is also incorporated herein byreference. A description of the holoreceptor transactivation assay isalso provided below.

HOLORECEPTOR TRANSACTIVATION ASSAY

CV1 cells (5,000 cells/well) were transfected with an RAR reporterplasmid aMTV-TREp-LUC (50 ng) along with one of the RAR expressionvectors (10 ng) in an automated 96-well format by the calcium phosphateprocedure of Heyman et al. Cell 68, 397-406. (8). For RXRtransactivation assays, an RXR-responsive reporter plasmid CRBPII-TK-LUC (50 ng) along with one of the RXR expression vectors (10 ng)was used substantially as described by Heyman et al. above, andAllegretto et al. J. Biol. Chem. 268, 26625-26633. (8, 9). RXR-reportercontained DRI elements from human CRBP II promoter (see Mangelsdorf etal. The Retinoids: Biology, Chemistry and Medicine, pp 319-349, RavenPress Ltd., New York and Heyman et al., cited above) (1, 8). Aβ-galactosidase (50 ng) expression vector was used as an internalcontrol in the transfections to normalize for variations in transfectionefficiency. The cells were transfected in triplicate for 6 hours,followed by incubation with retinoids for 36 hours, and the extractswere assayed for luciferase and β-galactosidase activities. The detailedexperimental procedure for holoreceptor transactivations has beendescribed in Heyman et al. above, and Allegretto et al. cited above. Theresults obtained in this assay in connection with examplary compounds inaccordance with the present invention are expressed in EC₅₀ numbers, asthey are also in the chimetic receptor transactivation assay. The Heymanet al. Cell 68, 397-406, Allegretto et al. J. Biol. Chem. 268,26625-26633, and Mangelsdorf et al. The Retinoids: Biology, Chemistryand Medicine, pp 319-349, Raven Press Ltd., New York, are expresslyincorporated herein by reference. The results of ligand binding assayare expressed in KD₅₀ numbers.

Table 2 below shows the results of the holoreceptor transactivationassay and Table 3 discloses the efficacy (in percentage) in this assayof the compound relative to all trans retinoic acid, for certainexemplary compounds of the invention. Table 4 shows the results of theligand binding assay for certain exemplary compounds of the invention.

                  TABLE 2                                                         ______________________________________                                        Holoreceptor Transactivation Assay                                            Compound EC.sub.50 (nanomolar)                                                #        RARα                                                                            RARβ                                                                             RARΓ                                                                          RXRα                                                                          RXRβ                                                                           RXRΓ                         ______________________________________                                        2        0.0     0.0     170   1.80  1.60  0.79                               6        2100    340     200   2400  2300  2500                               9        0.0     0.0     0.0   290   190   240                                13       0.0     0.0     0.0   130   100   71.0                               17       1200    48      270   30.0  19.0  13.0                               21       0.0     1800    0.0   27.0  25.0  29.0                               ______________________________________                                         0.0 in Table 2 indicates a value greater than 1000 nM                    

                  TABLE 3                                                         ______________________________________                                        Transactivation Assay Afficacy (% of RA activity)                             Compound                                                                      #        RARα                                                                            RARβ                                                                             RARΓ                                                                          RXRα                                                                          RXRβ                                                                           RXRΓ                         ______________________________________                                        2        10.0    15.0    28.00 76.00 110.0 68.0                               6        29.0    44.0    67.0  33.0  20.0  43.0                               9        2.0     8.0     8.0   59.0  94.0  50.0                               13       0.0     3.0     8.0   55.0  72.0  40.0                               17       30      29      41    111   118   73                                 21       4.0     26.0    14.0  83.0  93.0  85.0                               ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Ligand Binding Assay                                                          Compound KD.sub.50 (nanomolar)                                                #        RARα                                                                            RARβ                                                                             RARΓ                                                                          RXRα                                                                          RXRβ                                                                           RXRΓ                         ______________________________________                                        2        0.0     0.0     0.0   1.0   1.50  1.30                               13       0.0     0.0     0.0   71.0  56.0  42.0                               17       0.0     0.0     0.0   3.0   3.0   3.0                                21       0.0     0.0     0.0   5.0   6.0   12.00                              ______________________________________                                         0.0 in Table 4 indicates a value greater than 1000 nM                    

SPECIFIC EMBODIMENTS Synthetic Processes for Preparing Compounds of theInvention

The compounds of this invention can be made by a number of differentsynthetic chemical pathways. To illustrate this invention, there is hereoutlined a series of steps which have been proven to provide thecompounds of Formula 1 when such synthesis is followed in fact and inspirit. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by Formula 1.Furthermore, the synthetic chemist will readily appreciate that theherein described synthetic steps may be varied and or adjusted by thoseskilled in the art without departing from the scope and spirit of theinvention. ##STR7##

Referring now to Reaction Scheme 1 a primary or secondary alcohol ofFormula 10 is the starting material. The symbols Z, Y and R₁ in thisreaction scheme are defined as in connection with Formula 1. In thepresently preferred embodiments the R₁ group of Formula 10 is hydrogen,and therefore the starting material is a primary alcohol. Examples ofthe primary alcohols which are used for the preparation of the preferredcompounds of the present invention are 3-methyl-2(RS), 3(SR)-methano-35,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl!propan-1-ol,3-methyl-2(RS),3(RS)-methano-35,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!propan-1-ol,2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)benzylalcohol,3-methyl-2(RS),3(SR)-methano-34,4-dimethyl-thiochroman-6-yl!propan-1-ol,3-methyl-2(RS),3(SR)-methano-3 4,4-dimethyl-chroman-6-yl!propan-1-ol,2-(4,4-dimethyl-thiochroman-6-yl)benzyl alcohol,2-(4,4-dimethyl-chroman-6-yl)benzyl alcohol,3-methyl-2(RS),3(SR)-methano-3 4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl!propan-1-ol and 2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)benzyl alcohol. Examples of the startingalcohol of Formula 10 for the preparations of compounds of the inventionwhere Y is cyclopentyl or cyclohexyl are 2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-cyclopentyl!-methanol,2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-cyclohexyl!-methanol,2-(4,4-dimethyl-thiochroman-6-yl)cyclopentyl!-methanol,2-(4,4-dimethyl-thiochroman-6-yl)cyclohexyl!-methanol,2-(4,4-dimethyl-chroman-6-yl)cyclopentyl!-methanol,2-(4,4-dimethyl-chroman-6-yl)cyclohexyl!-methanol, 2-2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)cyclopentyl!-methanol,2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)cyclohexyl!-methanol.

The alcohol of Formula 10 is oxidized to provide the oxo compound ofFormula 11. The oxidation can be carried out with a number of oxidizingagents known in the art; one suitable condition employed for thesynthesis of the presently preferred embodiments is stirring the alcoholof Formula 10 with dimethylsulfoxide and trifluoroacetic anhydride. Theoxo compound (aldehyde when R₁ is H) of Formula 11 is not necessarilyisolated in an absolutely pure form, and can be used in a crude form inthe next coupling reaction with the diethylphosphono reagent of Formula12. The symbol R₁ in Formula 12 is defined as in connection with Formula1; in the preferred embodiments R₁ of Formula 12 is H or methyl. The B'group of Formula 12 is defined as the B group of Formula 1, or such aprotected derivative or precursor of B which can undergo and withstandthe conditions of the Horner Emmons coupling reaction and from which thedesired B group can be obtained by reactions well known to thepracticing organic chemist. Typically, and preferably the B' group is anesterified carboxylic acid; an example of the reagent used for thepreparation of the preferred compounds of the invention is ethyldiethylphosphono-3-methyl-2(E)-butenoate which can be obtained inaccordance with the chemical literature (J. Org. Chem. 1974 Volume 39 p.821). As is known in the art, the Horner Emmons reaction is conducted inthe presence of strong base (such as butyl lithium) in an inert solvent(such as tetrahydrofuran) and results in the formation of a double bondto replace the oxo function of the reagent of Formula 11. The resultingproduct is a diene of Formula 13, wherein the B' group represents the Bgroup of Formula 1 or a protected derivative thereof. In the preferredembodiments the B' or B group is a carboxylic acid or its ester, andtherefore the presently preferred compounds of the invention arederivatives of 2,4-pentadienoic acid. Instead of the Horner Emmonsreagent of Formula 12, an analogous Witng reagent can also be utilizedin the coupling reaction. The structure of such a Wittig reagent will bereadily apparent to those skilled in the art in light of the presentdisclosure. The herein described Horner Emmons coupling reactiontypically provides as predominant product the isomer where theconfiguration about the newly formed double bond ( ▴⁴ of thepentadienoic acid) is trans, and normally only this trans isomer isisolated from the reaction mixture. However, it is also possible toobtain a greater proportion of the corresponding cis isomer by adjustingconditions of the Horner Emmons reaction. As noted above, the B' groupof the compounds of Formula 13 can be subjected to such reactions whichare well within the skill of the practicing organic chemist, and whicheither result in the deprotection of B' to yield a B group within thescope of the invention, or which convert the B group into otherfunctions still within the scope of the invention. Examples of thelatter reactions are saponification, esterification,transesterification, amide formation, reduction to aldehyde andhomologation. These reactions are indicated in Reaction Scheme 1 byconversion to "homologs and derivatives". ##STR8##

Referring now to Reaction Scheme 2, a general synthetic route isdisclosed for obtaining the starting material used in the syntheticroute described in Reaction Scheme 1 for the situation where in theformula of the compounds of the invention Y represents an aryl orheteroaryl group. Such group is symbolized by Y, in the reaction scheme.In accordance with this scheme, a Grignard or like organometallicreagent of Formula 14 is prepared from a compound of the formula Z--Br,and the Grignard reagent is reacted with bromo (or other halogeno)compound of Formula 15 in the presence of zinc chloride andtriphenylphosphine nickel dichloride to obtain a carboxylate ester ofFormula 16. The Z group is defined as above in connection with Formula1.

An example of the reagent Z--Br utilized for the synthesis of certainpreferred compounds of the invention is2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (available inaccordance with the chemical literature, see Journal of MedicinalChemistry 1983 Vol. 26 p. 1653). Another example is 6- or7-bromo-4,4-dimethylchroman, and 6- or 7-bromo-4,4-dimethylthiochromanwhich are available in accordance with the teachings of U.S. Pat. Nos.5,348,972 and 5,053,523 the specifications of which is incorporatedherein by reference.

In order for the modified Grignard coupling reaction between thereagents of Formula 14 and Formula 15 to proceed well, the bromo atom ofthe compound of Formula 15 must be attached to an aromatic (orheteroaromatic) carbon, or to a vinylic carbon. For this reason, thereagent of Formula 15 is a brominated (or other halogenated)aryl-carboxylic acid ester, or bromo-heteroaryl carboxylic acid ester.These reagents are either commercially available, or generally speaking,can be prepared in accordance with the state of the art. An example forthe reagent of Formula 15 which is used for the synthesis of certainpreferred compounds of the invention is ethyl 2-bromobenzoate. Otherexamples for the reagent of Formula 15 are: ethyl2-bromo-pyridine-3-carboxylate, ethyl 2-bromothiophene-3-carboxylate andethyl 2-bromofuran-3-carboxylate.

The carboxylate ester product of Formula 16 is reduced with a suitablereducing agent, such as diisobutyl aluminum hydride (dibAlH) in an inertsolvent such as methylene chloride, to yield the primary alcohol ofFormula 10 where R₁ is hydrogen. The primary alcohol of Formula 10 isthe starting material indicated in Reaction Scheme 1. The carboxylateester compound of Formula 16 can also be converted to a ketone by aGrignard or modified Grignard reaction to yield the compounds of Formula11 where the R₁ group is lower alkyl. The ketone compounds of Formula 11can also serve in accordance with Reaction Scheme 1 for the synthesis ofthe compounds of the invention.

The synthetic methodology described above in connection with ReactionScheme 2 is also suitable for preparation of compounds of the inventionwhere the Y group is cycloalkyl, other than cyclopropyl. In such case, abrominated cycloalkenyl carboxylate ester of Formula 17 is reacted withthe Grignard (or like organometallic) reagent of Formula 14 in thepresence of zinc chloride and his triphenyl phosphine nickel (II)chloride to provide compounds of Formula 18. Examples of reagents ofFormula 17 are ethyl 2-bromocyclohexene carboxylate and ethyl2-bromocyclopentene carboxylate. Accordingly, the Y" in Formula 17represents a cycloalkene ring. Compounds of Formula 18 are subjected tohydrogenation to saturate the double bond in the cycloalkene ring, andthereafter reduced with diisobutyl aluminum hydride (dibAlH) to yieldthe primary alcohols of Formula 10. Y'" of Formula 19 of Reaction Scheme2 represents a cycloalkyl ring. Compounds of Formula 17 can also bereduced to the alcohols of Formula 10 and follow Reaction Scheme 1 toprovide cycloalkenyl compounds of the invention, as defined in Formula 1where Y is cycloalkenyl. ##STR9##

Reaction Scheme 3 discloses a synthetic route for the preparation of thestarting primary alcohol (in accordance with Formula 10) for thesynthesis of the preferred compounds of the invention where the Y groupof Formula 1 is methylcyclopropyl. In accordance with this reactionscheme, an ethyne compound of the formula Z--C≡CH (Formula 20) isreacted with ethyl chloroformate (or methylchloroformate) in thepresence of strong base (butyl lithium) in an inert solvent (such ashexane) to yield the propiolate compound of Formula 21. The ethynecompounds of Formula 20 are, generally speaking, known in the art. Anexamplary compound of Formula 20 which is used for the synthesis of theherein described preferred embodiments is2-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene which can beobtained in accordance with the chemical literature, see The Retinoid:Biology, Chemistry and Medicine 2nd Edition, Editors Sporn et al., RavenPress Ltd. N.Y. 1994, Chapter 2, pg 157. Further examples are(4,4-dimethyl-thiochroman-6-yl)ethyne, (4,4-dimethylchroman-6-yl)ethyne,(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethyne,(2,2,4,4-tetramethyl-thiochroman-6-yl)ethyne,(2,2,4,4-tetramethyl-chroman-6-yl)ethyne,(2,2,4,4-tetramethyl-1,2,3,4-tetrahydro-quinolin-6-yl)ethyne, which canbe obtained in accordance with the teachings of U.S. Pat. Nos.5,053,523, 5,278,318, 5,346,895 and 5,348,972, the specifications ofwhich is incorporated herein by reference. The propiolate compound ofFormula 21 is thereafter reacted with methyl lithium in the presence ofcopper(I)bromide-dimethylsulfide in an inert solvent such astetrahydrofuran. The reaction results in addition of the methyl group tothe double bond, to yield the enoate compound of Formula 22. Dependingon the reaction conditions which are described in detail below in thedescription of the specific embodiments, compounds of Formula 22 of bothcis and trans orientation about the double bond can be obtained in thismanner. The enoate compound of Formula 22 is thereafter reduced with asuitable reagent, such as diisobutyl aluminum hydride, to yield theprimary alcohol of Formula 23. In the next step, the double bond of thealcohol of Formula 23 is converted into a cyclopropyl ring in acyclopropylation reaction which employs the reagent diiodomethane in thepresence mercury(II)chloride, and samarium. The cyclopropylationreaction is usually conducted at cold temperature (-78° C.), in an inertsolvent such as tetrahydrofuran in an inert (argon) gas atmosphere. Inthe cyclopropylation reaction the orientation (cis or trans) of thedouble bond to which the methylene group is attached, is maintained, sothat from a cis allylic alcohol of Formula 23 a cis cyclopropylderivative is obtained, whereas a trans allylic alcohol of Formula 23yields a trans cyclopropyl derivative. The product of thecyclopropylation reaction is the alcohol of Formula 10 (where Y ismethylcyclopropyl) which is used as the starting compound for thesynthesis of the compounds of the invention in accordance with ReactionScheme 1. The unsaturated alcohol of Formula 23 (or preferably an esterthereof) can also be reacted with a diene compound (such as1,3-butadiene) under Diels Alder conditions (heating in a sealed tube)to yield a cyclohexene derivative of Formula 24, which, after saturationof the double bond by hydrogenation, yields the alcohol of Formula 10,where Y is methyl cyclohexyl.

Referring now back to Reaction Scheme 1 and to the preparation ofhomologs and derivatives of the compounds of the invention, as well asto transformations of the B' group which may become necessary to obtaina desired reagent in accordance with Formula 12, where such reagent isnot available commercially or from a known literature procedure, thefollowing synthetic methodology is noted.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, "AdvancedOrganic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

The acids and salts derived from compounds of Formula 1 are readilyobtainable from the corresponding esters. Basic saponification with analkali metal base will provide the acid. For example, an ester ofFormula 1 may be dissolved in a polar solvent such as an alkanol,preferably under an inert atmosphere at room temperature, with about athree molar excess of base, for example, lithium hydroxide or potassiumhydroxide. The solution is stirred for an extended period of time,between 15 and 20 hours, cooled, acidified and the hydrolysate recoveredby conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with a 10-fold excess of oxalylchloride. This is effected at a moderately reduced temperature betweenabout -10 degrees and +10 degrees C. The last mentioned solution is thenstirred at the reduced temperature for 1-4 hours, preferably 2 hours.Solvent removal provides a residue which is taken up in an inert organicsolvent such as benzene, cooled to about 0 degrees C and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alky halides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

SPECIFIC EMBODIMENT 8 Ethyl3-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propiolate(Compound A)

To a cold solution (-78° C.) of 2-ethynyl,5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (900 mgs, 4.3 mmols) in ether (20 ml) wasadded n-butyllithium in hexane (5.6 mmols). The mixture was stirred for45 mins, and ethylchloroformate (1.3 g, 12 mmols) was added via syringe.Stirring was continued for 45 mins then the mixture was warmed graduallyto -10° C. and quenched by adding sodium bicarbonate (NaHCO₃) solution(10 ml). Diethyl ether (100 ml) was added, the organic phase washed withwater (10 ml), brine (10 ml), and dried (MgSO4). The solvent was removedin vacuo. Purification of the residue over silicagel (5% ethylacetate inhexane) gave the title compound as a colorless oil.

PMR (CDCl₃): δ 1.27 (12H, s), 1.36 (3H, t, j=7.5 Hz), 1.68 (4H, s), 4.29(2H, q, j=7.5 Hz), 7.30 (1H, d, j=8.2 Hz), 7.35 (1H, dd, j=1.6, 8.2 Hz),7.56 (1H, d, j=1.6 Hz).

Ethyl3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)but-2(Z)-enoate(Compound B)

To a cold (-20° C.) solution of copper(I)bromidedimethylsulfide(CuBr.DMS) (832 mgs, 4.06 mmols) in THF (30 ml) methyllithium in ether(7.95 mmols) was added dropwise. The clear solution was stirred for 10mins, then cooled to -78° C. To this solution ethyl3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth-2-yl)propiolate(Compound A, 900 mgs, 2.9 mmols) in THF (5 ml) was added dropwise (10mins). The mixture was stirred for additional 2 hours at -78° C. Thereaction was quenched by slow addition of ethanol to the cold (-78° C.)solution, followed by water (10 ml), and the mixture was diluted withmore water (100 ml). The organic phase was washed with 10% HCl (10 ml),brine (10 ml) and dried (MgSO4). The solvent was removed in vacuo togive the title compound as a colorless oil.

PMR (CDCl3): δ 1.03 (3H, t, j=7.5 Hz), 1.26 (6H, s), 1.28 (6H, s), 1.68(4H, s), 2.17 (3H, d, j=i.4 Hz), 3.98 (2H, q, j=7.5 Hz), 5.86 (1H, q,j=1.4 Hz), 6.96 (1H, dd, j=2.0, 8.1 Hz), 7.14 (1H, d, j=2.0 Hz), 7.26(1H, d, j=8.1 Hz).

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-en-1-ol(Compound C)

To a cold (-78° C.) solution of ethyl 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)but-2(Z)-enoate (Compound B 500 mgs, 1.66mmols) in THF (20 ml) was added DibAl-H in methylene chloride (6 mmols)dropwise (5 mins). The mixture was gradually (4 hours) allowed to warmto -10° C. The reaction was quenched by adding methanol (2 ml) followedby 10% HCl, and the mixture was stirred for 5 mins, then diethyl ether(100 ml) was added. The organic phase was washed with water (10 ml), 10%NaHCO₃ (10 ml) and brine (10 ml) and dried (MgSO₄). The solvent wasremoved in vacuo to afford the title compound as a colorless oil.

PMR (CDCl₃): δ 1.28 (6H, s), 1.29 (6H, s), 1.69 (4H, s), 2.10 (3H, brs),4.13 (2H, d, j=6.9 Hz), 5.69 (1H, t, j=6.9 Hz), 6.96 (1H, dd, j=2.1, 8.2Hz), 7.09 (1H, d, j=2.1 Hz), 7.26 (1H, d, j=8.2 Hz).

3-Methyl-2(RS),3(SR)-methano-3(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propan-1-ol(Compound D)

To a flame dried round bottom flask containing samarium (1.125 g, 7.5mmols) under argon atmosphere was added THF (10 ml), mercury(II)chloride(203 mgs, 0.75 mmol) in THF (10 ml) and 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)but-2(Z)-en-1-ol (Compound C 390 mgs, 1.5mmols) in THF (5 ml), sequentially. The mixture was cooled to -78° C.and diiodomethane (2.01g, 7.5 mmols) was added via syringe. The mixturewas stirred and gradually warmed to ambient temperature (4h). Thereaction was quenched by adding potassium carbonate solution (15 ml) andextracted with diethyl ether (5×25 ml). The organic phase was washedwith water (10 ml), brine (10 ml) and dried (MgSO₄). The solvent wasremoved in vacuo, and purification of the residue by silicagelchromatography (5% ethylacetate in hexane) gave the title compound as acolorless oil.

PMR (CDCl₃): δ 0.72-0.79 (1H, m), 0.83-0.91 (1H, m), 1.22-1.23 (1H, m)1.26 (6H, s), 1.27 (6H, s), 1.40 (3H, s), 1.67 (4H, s), 3.12-3.22 (1H,m), 3.26-3.34 (1H, m), 7.06 (1H, dd, j=1.9, 8.1 Hz), 7.21 (1H, d, 8.1Hz), 7.23 (1H, brs).

Ethyl 3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoate (Compound 1)

To a cold (-70° C.) solution of dimethylsulfoxide (DMSO) (1.09 g, 14mmols) in methylene chloride (10 ml) was added a solution oftrifluoroacetic anhydride (2.52 g, 12 mmols) in methylene chloride (3ml) dropwise (3 mins). To the stirred (10 mins) mixture was added asolution of 3-methyl-2(RS),3(SR)-methano-3(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propan-1-ol (Compound D, 598 mgs, 2.2 mmols)in methylene chloride (3 ml) dropwise. The mixture was stirred foradditional 30 mins, then triethylamine (3.5 g, 35 mmols) in methylenechloride (5 ml) was added to it. The reaction mixture was allowed towarm to 0° C. (over 20 mins) and diluted with methylene chloride (60ml). The organic phase was washed with water (10 ml), sodium bicarbonate(10 ml) and dried (MgSO₄). The solvent was removed in vacuo. Silicagelchromatography (5% ethyl acetate in hexane) of the crude product gave3-methyl-2(RS),3(SR)-methano-3(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propionaldehyde. Thisunstable product was dissolved in dry THF (5 ml) and was added to a cold(-78° C.) solution of ethyl diethylphosphono-3-methyl-2(E)-butenoate(792 mgs, 3 mmols) and n-butyllithium (2.88 mmols) in THF (10 ml). Themixture was stirred for 10 mins and quenched by adding water (10 ml) anddiluted with diethyl ether (60 ml). The organic layer was washed withbrine (10 ml) and dried (MgSO₄). The solvent was removed under reducedpressure. The crude product was purified by silicagel chromatography (3%ethylacetate in hexane) followed by HPLC (2% ethylacetate in hexane) togive the title compound as a colorless oil.

PMR (CDCl₃): δ 1.11-1.20 (2H, m), 1.21 (3H, s), 1.28 (9H, s), 1.28 (3H,t, j=7.2 Hz), 1.43 (3H, s), 1.68 (4H, s), 1.68-1.80 (1H, m), 1.99 (3H,s), 4.15 (2H, q, j=7.2 Hz), 5.22 (1H, dd, j=9.9, 15.4 Hz), 5.63 (1H, s),6.20 (1H, d, j=15.4 Hz), 7.03 (1H, dd, j=1.9, 8.1 Hz), 7.14 (1H, d,j=l.9 Hz), 7.23 (1H, d, j=8.1 Hz).

3,7-Dimethyl,6(RS),7(SR)methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoic acid (Compound 2)

To a solution of ethyl 3,7-dimethyl,6(RS),7(SR)methano-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth-2-yl),2(E),4(E)-heptadienoate (Compound 1 104 mgs, 027 mmols), in THF (2 ml)and methanol (1 ml) was added lithium hydroxide (1 mmol) in water, andthe mixture was stirred at ambient temperature for 24 hours. Thereafterdiethyl ether (60 ml) was added, the mixture was acidified with 10% HCl,and the organic phase was washed with water (5 ml), brine (5 ml), dried(MgSO₄) and the solvent was removed in vacuo. Chromatography onsilicagel (25% ethylacetate in hexane) gave the title compound as awhite solid.

PMR (CDCl₃): δ 1.12-1.22 (2H, m), 1.20 (3H, s), 1.27 (9H, s), 1.43 (3H,s), 1.67 (4H, s), 1.68-1.77 (1H, m), 1.98 (3H, s), 5.27 (1H, dd, j=9.9,15.5 Hz), 5.65 (1H, s), 6.21 (1H, d, j=15.5 Hz), 7.03 (1H, dd, j=1.8,8.0 Hz), 7.13 (1H, d, j=i. SHz), 7.23 (1H, d, j=8.0 Hz).

Ethyl3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)but-2(E)-enoate(Compound E)

Employing the same general procedure as for the preparation of ethyl3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)but-2(Z)-enoate(Compound B), but instead using 900 gs (2.9 mmols) of ethyl3-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propiolate(Compound A), 832 mgs (4.06 mmols) of CuBr(I).DMS, 5.6 mmols ofmethyllithium in ether and maintaining the temperature at 0° C. thetitle compound was obtained as a colorless oil.

PMR (CDCl₃): δ 1.29 (6H, s), 1.31 (6H, s), 1.33 (3H, t, j=7.1 Hz), 2.57(3H, d, j=1.5 Hz), 4.22 (2H, q, j=7.1 Hz), 6.11 (1H, d, j=1.5 Hz), 7.25(1H, dd, j=1.8, 8.3 Hz), 7.31 (1H, d, j=8.3 Hz), 7.41 (1H, d, j=1.8 Hz).

3-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl) but-2(.Z)-en-1-ol(Compound F)

Employing the same general procedure as used for the preparation of3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl) but-2(Z)-en-1-ol(Compound C), but instead using 500 mgs (1.66 mmols) of ethyl3-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphth-2-yl)-but-2(E)-enoate(Compound E) and 6 mmols of diisobutylaluminiumhydride the titlecompound was obtained as a colorless oil.

PMR (CDCl₃): δ 1.29 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.08 (3H, s),4.37 (12H, t, j=6.5 Hz), 5.90-5.99 (1H, m), 7.18 (1H, dd, j=1.8, 8.2Hz), 7.27 (1H, d, j=8.2 Hz), 7.35 (1H, d, j=1.8 Hz).

(+/-)3-Methyl-2(RS),3(RS)-methano-3(5,5,8,8-tetramethy1-5,6,7,8-tetrahydronaphth-2-yl)propan-1-ol (Compound G)

Employing the same general procedure as used for the preparation of3-methyl-2(RS),3(SR)-methano-3(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth-2-yl)propan-1-ol (Compound D),but instead using 390 mgs (1.5 mmols) of3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth-2-yl) but-2(Z)-en-1-ol(Compound F), 1.125 g (7.5 mmols) of samarium, 203 mgs (0.75 mmol) ofmercuric chloride and 2.01 g (7.5 mmols) of diiodomethane title compoundwas obtained as a colorless oil.

PMR (CDCl₃): δ 0.59 (1H, t, j=5.4 Hz), 1.12 (1H, dd, j=4.7, 8.9 Hz),1.27 (6H, s), 1.29 (6H, s), 1.40-1.48 (1H, m), 1.46 (3H, s), 1.68 (4H,s), 3.65-3.78 (1H, m), 3.85-3.92 (1H, m), 7.02 (1H, dd, j=2.1, 8.2 Hz),7.18 (1H, d, j=2.1 Hz), 7.23 (1H, d, j=8.2 Hz),

Ethyl 3,7-dimethyl,6(RS),7(RS) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(Z),4(E)-heptadienoate (Compound 3) andEthyl 3,7-dimethyl,6(RS),7(RS)methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E!-heptadienoate (Compound 4)

Employing the same general procedure as used for the preparation ofethyl 3,7-dimethyl,6(RS),7(SR)methano-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl),2(E),4(E)-heptadienoate (Compound 1), but instead using 300 mgs (1.1mmols) of 3-methyl-2(RS), 3(RS)-methano-35,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-naphth-2-yl!propan-1-ol(Compound G), the starting compound was converted to the isomeric titlecompounds in the ratio of 4 (Compound 4) :1 (Compound 3).

Ethyl 3,7-dimethyl,6(RS),7(RS) methano-7- (5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl),2(Z),4(E)-heptadienoate (Compound 3)

PMR (CDCl₃): δ 0.96 (1H, t, j=5.2 Hz), 1.28 (6H, s), 1.29 (6H, s), 1.29(3H, t, j=7.5 Hz), 1.45 (3H, s), 1.51 (1H, dd, j=4.9, 8.6 Hz), 1.68 (4H,s), 1.88-1.98 (1H, m), 2.03 (3H, s), 4.28 (2H, q, j=7.5 Hz), 5.59 (1H,s), 6.04 (1H, dd, j=9.0, 15.7 Hz), 7.01 (1H, dd, j=2.0, 8.2 Hz), 7.17(1H, d, j=2.0 Hz), 7.23 (1H, d, j=8.2 H*z), 7.77 (1H, d, j=15.7 Hz).

Ethyl 3,7-dimethyl,6(RS),7(RS) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoate (Compound 4 )

PMR (CDCl₃): δ 0.94 (1H, t, j=5.5 Hz), 1.27 (6H, s), 1.29 ((6H, s), 1.29(3H, t, j=7.1 Hz), 1.45 (3H, s), 1.51 (1H, dd, j=4.9, 8.5 Hz), 1.68 (4H,s), 1.78-1.88 (1H, m), 2.31 (3H, s), 4.17 (2H, q, j=7.1 Hz), 5.72 (1H,s), 6.01 (1H, dd, j=9.0, 15.4 Hz), 6.28 (1H, d, j=15.4 Hz), 7.00 (1H,dd, j=2.1, 8.3 Hz), 7.17 (1H, d, j=2.1 Hz), 7.23 (1H, d, j=8.3 Hz).

3,7-Dimethyl, 6(RS),7(RS) methano-7- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(Z),4(E)-heptadienoic acid (Compound 5)

Employing the same general procedure as used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 30 mgs of ethyl 3,7-dimethyl,6(RS),7(RS)methano-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl),2(Z),4(E)-heptadienoate (Compound 3), and LiOH in water (1M solution, 1ml ), THF (2 ml), methanol (2 ml) the title compound was obtained as awhite solid (21 mgs).

PMR (CDCl₃); δ 0.98 (1H, t, j=5.5 Hz), 1.28 (6H, s), 1.29 (3H, s), 1.30(3H, s), 1.46 (3H, s), 1.54 (1H, dd, j=4.9, 8.6 Hz), 1.68 (4H, s),1.89-1.97 (1H, m), 2.06 (3H, s), 5.61 (1H, s), 6.09 (1H, dd, j=9.2, 15.7Hz), 7.01 (1H, dd, j=2.1, 8.2 Hz), 7.17 (1H, d, j=2.1 Hz), 7.24 (1H, d,j=8.2 Hz), 7.74 (1H, d, j=15.7 Hz).

3,7-Dimethyl,6(RS),7(RS) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E) -heptadienoic acid (Compound 6)

Employing the same general procedure used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 100 mgs of ethyl 3,7-dimethyl,6(RS),7(RS)methano-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth-2-yl),2(E),4(E)-heptadienoate (Compound 4), and LiOH in water (1M solution, 2ml), THF (4 ml), methanol (2 ml) gave the title compound was obtained asa white solid.

PMR (CDCl₃): δ 0.95 (1H, t, j=5.4 Hz), 1.27 (6H, s), 1.28 (3H, s), 1.29(3H, s), 1.45 (3H, s), 1.52 (1H, dd, j=5.0, 8.4 Hz), 1.68 (4H, s),1.80-1.89 (1H, m), 5.74 (1H, s), 6.07 (1H, dd, j=9.2, 15.4 Hz), 6.32(1H, d, j=15.4 Hz), 7.00 (1H, dd, j=2.0, 8.3 Hz), 7.16 (1H, d, j=2.0Hz), 7.24 (1H, d, j=8.3 Hz).

Ethyl 2- 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!benzoate(Compound H)

To magnesium (180 mgs, 7.5 mmols) in THF (3 ml) was added a solution of2 -bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (200 mgs) inTHF (5 ml) followed by 1,2-dibromoethane (94 mgs, 0.5 mmol). The mixturewas stirred for 15 mins, then another portion of2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (1.14 g, 5mmols) in THF (10 ml) was added. The mixture was stirred for 15 mins atroom temperature, and refluxed for 1 h. ZnCl₂ (680 mgs, 5 mmols) wasadded, stirred for 40 mins, and to the white precipitate.ethyl-2-bromobenzoate (1.09 g) in THF (5 ml) was added, immediatelyfollowed by addition of Ni(PPh₂ CH₂ CH₂)Cl₂ (26 mgs, 0.05 mmols). Themixture was stirred at room temperature for 16h. The reaction mixturewas diluted with diethyl ether:ethylacetate (1:1, a total of 180 ml),the organic phase was washed with water (10 ml), brine (10 ml) NaHCO₃(10 ml) and brine (10 ml), dried (MgSO₄) and the solvent was removedunder reduced pressure. Silicagel chromatography (5% ethyl acetate inhexane) followed by HPLC purification of the crude material gave thetitle compound as a colorless oil.

PMR (CDCl₃): δ 0.89 (3H, t, j=7.1 Hz), 1.29 (6H, s), 1.31 (6H, s), 4.04(2H, q, j=7.1 Hz), 7.09 (1H, dd, j=2.0, 8.1 Hz), 7.22 (1H, d, j=2.0 Hz),7.33 (1H, d, j=8.1 Hz), 7.40 (2H, d, j=6.9 Hz), 7.46-7.55 (1H, m), 7.76(1H, d, j=7.1 Hz).

2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)benzylalcohol(Compound I)

Employing the same general procedure as used for the preparation of3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl) but-2(Z)-en-1-ol(Compound C), but instead using 420 mgs (1.25 mmols) ethyl 2-5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl!benzoate (Compound H)and 6 mmols of diisobutylaluminiumhydride the title compound wasobtained as a white solid.

PMR (CDCl₃): δ 1.36 (6H, s), 1.39 (6H, s), 1.79 (4H, s), 4.67 (2H, s),7.17 (1H, d, j=7.9 Hz), 7.34-7.44 (5H, m), 7.55-7.61 (1H, m).

Ethyl 3-methyl-5- 2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl!pent-2 (E),4(E)-dienoate (Compound 7) and Ethyl 3-methyl-5-2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl!pent-2(Z),4(E)-dienoate (Compound 8)

Employing the same general procedure as used for the preparation ofethyl 3,7-dimethyl,6(RS),7(SR)methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoate (Compound 2), but instead using 292 mgs (1 mmol) of 2-5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl!benzylalcohol(Compound I), the starting material was converted to the isomeric titlecompounds in the ratio of 8 (Compound 7) :1 (Compound 8).

Compound 7

PMR (CDCl₃): δ 1.25 (6H, s), 1.28 (3H, t, j=7.1 Hz), 1.32 (6H, s), 1.70(4H, s), 2.22 (3H, brs), 4.16 (2H, q, j=7.1 Hz), 5.87 (1H, brs), 6.74(1H, d, j=16.1 Hz), 7.01 (1H, d, j=16.1 Hz), 7.11 (1H, dd, j=1.8, 7.9Hz), 7.22 (1H, d, j=1.8 Hz), 7.30-7.38 (4H, m), 7.59-7.69 (1H, m).

Compound 8

PMR (CDCl₃): δ 1.29 (6H, s), 1.33 (3H, t, j=7.2 Hz), 1.35 (6H, s), 1.73(4H, s), 1.96 (3H, s), 4.22 (2H, q, j=7.2 Hz), 5.71 (1H, s), 7.03 (1H,d, j=16.3Hz), 7.15 (1H, dd, j=2.0, 8.1 Hz), 7.26 (1H, d, j=2.0 Hz),7.32-7.39 (4H, m), 7.80-7.88 (1H, m), 8.39 (1H, d, j=16.3 Hz).

3-Methyl-5-2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl!pent-2(E),4(E)-dienoicacid (Compound 9)

Employing the same general procedure used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 100 mgs of ethyl 3-methyl-5-2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl!pent-2(E),4(E)dienoate (7) and LiOH inwater (1M solution, 1.5 ml), THF (2 ml), methanol (2 ml) the titlecompound was obtained as a white solid.

PMR (CDCl₃): δ 1.28 (6H, s), 1.35 (6H, s), 1.73 (4H, s), 2.26 (3H, s),5.93 (1H, s), 6.79 (1H, d, j=16.1 Hz), 7.10 (1H, d, j=16.1 Hz), 7.14(1H, dd, j=1.8, 8.2 Hz), 7.25 (1H, d, j=1.8 Hz), 7.34-7.41 (4H, m),7.64-7.71 (1H, m).

3-Methyl-5-(2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phen-1-yl) pent-2(Z),4(E)-dienoic acid (Compound 10)

Employing the same general procedure as used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 20 mgs of ethyl 3-methyl-5-2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl!pent-2(Z),4(E)dienoate (Compound 8) andLiOH in water (1M solution, 0.5 ml), THF (2 ml), methanol (2 ml) thetitle compound was obtained as a white solid.

PMR (CDCl₃): δ 1.30 (6H, s), 1.35 (6H, s), 1.74 (4H, s), 2.00 (3H, s),5.75 (1H, s), 7.09 (1H, d, j=15.9 Hz), 7.15 (1H, dd, j=1.7, 8.2 Hz),7.32-7.41 (4H, m), 7.78-7.83 (1H, m), 8.32 (1H, d, j=15.9 Hz).

Ethyl 3- 3,5,5,8,8,-Dentamethyl-5,6,7,8-tetrahydronaphth-2-yl!propiolate(Compound J)

Employing the same general procedure as used for the preparation ofethyl 3- 5,5,8,8,-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl!propiolate(Compound A), but instead using 1.9 g of(3-methyl-5,5,8,8,-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl)ethyne,940 mgs (10 mmols) of methylchloroformate and 8.8 mmols ofn-butyllithium the title compound was obtained as an oil.

PMR (CDCl₃): δ 1.26 (6H, s), 1.27 (6H, s), 1.67 (4H, s), 2.43 (3H, s),3.85 (3H, s), 7.16 (1H, s), 7.51 (1H, s).

Methyl 3-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-enoate(Compound K)

Employing the same general procedure as for the preparation of ethyl 3-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-enoate(Compound B), but instead using 2.05 gs (6.4 mmols) of methyl 3-3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!propiolate(Compound J), 2.1 gs (10.24 mmols) of CuBr.DMS, 18 mmols of methyllithium in diethyl ether and maintaining the temperature at -78° C. thetitle compound was obtained as a white solid.

PR (CDCl₃): δ 1.24 (6H, s), 1.28 (6H, s), 1.67 (6H, s), 2.12 (3H, s),2.15 (3H, s), 3.50 (3H, s), 5.96 (1H, s), 6.86 (1H, s), 7.08 (1H, s).

3- 3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-en-1-ol(Compound L)

Employing the same general procedure as used for the preparation of3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl) but-2(Z)-en-1-ol(Compound C), but instead using 1.85 gs (6.1 mmols) of methyl 3-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-enoate(Compound K) and 15 mmols of diisobutylaluminiumhydride the titlecompound was obtained as a white solid.

PMR (CDCL₃): δ 1.25 (6H, s), 1.28 (6H, s), 1.67 (4H, s), 2.00 (3H, s),2.16 (3H, s), 3.84 (2H, d, j=7.1 Hz), 5.73 (1H, dt, j=1.6, 7.1 Hz), 6.90(1H, s), 7.08 (1H, s).

3-Methyl-2(RS),3(SR)-methano-3 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!propan-1-ol (Compound M)

Employing the same general procedure as used for the preparation of3-methyl-2(RS),3(SR)-methano-3,5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!propan-1-ol (Compound D),instead using 1.1 gs (4 mmols) of 3-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-en-1-ol(Compound L), 3.1 g (20.6 mmols) of samarium, 450 mgs (1.7 mmol) ofmercuric chloride and 5.8 g (21.6 mmols) of diiodomethane the titlecompound was obtained as a colorless oil.

PMR (CD₃ COCD₃): δ 0.60 (1H, brs), 0.80 (1H, brs), 1.23 (9H,s), 1.24(3H, s), 1.64 (4H, s), 1.63-1.67 (1H, m), 2.33 (3H, s), 2.85 (3H, s),3.34-3.48 (2H, m), 7.06 (1H, s), 7.25 (1H, brs).

Ethyl 3,7-dimethyl,6(RS),7(SR) methano-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoate (Compound 11) andEthyl 3,7-dimethyl,6(RS),7(SR) methano-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydrqnaphth-2-yl),2(Z),4(E)-heptadienoate (Compound 12)

Employing the same general procedure as used for the preparation ofethyl 3,7-dimethyl,6(RS),7(SR)methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoate (Compound 2), but instead using 390 mgs (1.4mmols) of 3-methyl-2(RS),3(RS)-methano-3 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl!propan-1-ol (compound M), the startingmaterial was converted to the isomeric title compounds in the ratio of 8(Compound 11): 1(Compound 12).

Compound 11

PMR (CDCl₃): δ 0.96 (1H, brs), 1.20 (1H, brs), 1.25 (3H, s), 1.26 (3H,s), 1.27 (6H, s), 1.29 (3H, t, j=7.1 Hz), 1.37 (3H, s), 1.66 (4H, s),1.70-1.80 (1H, m), 2.04 (3H, brs), 2.31 (3H, brs), 4.16 (2H, q, j=7.1Hz), 5.30 (1H, brs), 5.66 (1H, brs), 6.25 (1H, d, j=15.5 Hz), 7.04 (1H,s), 7.07 (1H, brs).

Compound 12

PMR (CDCl₃): δ 0.95 (1H, brs), 1.19 (1H, brs), 1.23 (3H, s), 1.25 (9H,s), 1.30 (3H, t, j=7.1 Hz), 1.35 (3H, s), 1.64 (4H, s), 1.71 (3H, brs),1.80-1.90 (1H, m), 2.31 (3H, BRS), 4.17 (2H, q, j=7.1 Hz), 5.31 (1H,brs), 5.49 (1H, s), 7.02 (1H, s), 7.08 (1H, brs), 7.78 (1H, d, j=15.6Hz).

3,7-Dimethyl,6(RS),7(SR) methano-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoic acid (Compound 13)

Employing the same general procedure as used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 100 mgs of ethyl3,7-dimethyl,6(RS),7(RS)methano-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoate (Compound 4) and LiOH in water (1M solution, 1ml), THF (4 ml), methanol (2 ml) the title compound was obtained as awhite solid.

PMR (CD₃ COCD₃): δ 1.01 (1H, brs), 1.18 (1H, s), 1.21 (3H, s), 1.23 (3H,s), 1.24 (6H, s), 1.33 (3H, s), 1.64 (4H, s), 1.70-1.86 (1H, m), 1.97(3H, brs), 2.29 (3H, brs), 5.31 (1H, brs), 5.68 (1H, s), 6.31 (1H, d,j=15.8 Hz), 7.09 (2H, s).

3,7-Dimethyl, 6(RS),7(SR) methano-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl),2(Z),4(E)-heptadienoic acid (Compound 14)

Employing the same general procedure as used for he preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 12 mgs of ethyl3,7-dimethyl,6(RS),7(RS)methano-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl),2(Z),4(E)-heptadienoate (Compound 12) and LiOH in water (1M solution inwater 0.4 ml) the title compound was obtained as a white solid.

PMR (CDCl₃): δ 1.01 (1H, brs), 1.20 (1H, s), 1.24 (12H, s), 1.35 (3H,s), 1.66 (4H, s), 1.79-1.89 m), 2.30 (3H, brs) 2.83 (3H, brs), 5.30(1H,brs), 5.52 (1H, s), 7.10 (2H, brs), 7.81 (1H, d, j=16.4 Hz).

Methyl 3-(4,4-dimethyl-thiochroman-6-yl)propiolate (Compound N)

Employing the same general procedure as used for the preparation ofethyl 3-(5,5,8,8,-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl)propiolate(Compound A), but instead using 2.0 g (10 mmols) of(4,4-dimethylthiochroman-6-yl)ethyne, 2 g (21.3 mmols) ofmethylchloroformate and 11 mmols of n-butyl lithium the title compoundwas obtained as a yellow solid.

PMR (CDCl₃): δ 1.31 (6H, s), 1.90-1-1.97 (2H, m), 3.00-3.07 (2H, m),3.83 (3H, s), 7.07 (1H, d, j=8.1 Hz), 7.22 (1H, dd, j=1.8, 8.1 Hz), 7.57(1H, d, j=1.8 Hz).

Methyl 3- 4,4-dimethyl-thiochroman-6-yl!but-2(Z)-enoate (Compound O)

Employing the same general procedure as for the preparation of ethyl 3-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-enoate(Compound B), but instead using 1.6 g (6.1 mmols) of methyl 3-4,4-dimethyl-thiochroman-6-yl!propiolate (Compound N), 2.1 g (10.24mmols) of CuBr. DMS, 18 mmols of methyl lithium in ether and maintainingthe temperature at -78° C., the title compound was obtained as acolorless oil.

PMR (CDCl₃): δ 1.33 (6H, s), 1.97 (2H, t, j=6.0 Hz), 3.03 (2H, t, j=6.0Hz), 3.58 (3H, s), 5.87 (1H, s), 6.93 (1H, dd, j=1.9, 8.1 Hz), 7.05 (1H,d, j=8.1 Hz), 7.24 d, j=1.9 Hz).

3- 4,4-Dimethyl-thiochroman-6-yl!but-2(Z)-en-1-ol (Compound P)

Employing the same general procedure used for the preparation of 3-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!but-2(Z)-en-1-ol(Compound C), but instead using 1.3 g (4.7 mmols) of methyl 3-4,4-dimethyl-thiochroman-6-yl!but-2(Z)-enoate (Compound O) and 15 mmolsof diisobutylaluminiumhydride the title compound was obtained as acolorless oil.

PMR (CDCl₃): δ 1.34 (6H, s), 1.95-2.00 (2H, m), 2.08 (3H, s), 3.01-3.05(2H, m), 4.10 (2H, d, j=7.0 Hz), 5.67 (1H, d, J=7.0 Hz), 6.87 (1H, dd,j=2.0, 8.1 Hz), 7.05 (1H, d, j=8.1 Hz), 7.17 (1H, d, j=2.0 Hz).3-Methyl-2(RS),3(SR)-methano-3 4,4-dimethyl-thiochroman-6-yl!propan-1-ol(Compound O)

Employing the same general procedure as used for the preparation of3-methyl-2(RS),3(SR)-methano-3 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl!propan-1-ol (Compound D),but instead using 1.23 g (4.5 mmols) of 3-4,4-dimethyl-thiochroman-6-yl!but-2(Z)-en-1-ol (Compound P), 3.95 g(26.3 mmols) of samarium, 520 mgs (1.92 mmols) of mercuric chloride and6.95 g (25.9 mmols) of diiodomethane the title compound was obtained asa colorless oil.

PMR (CDCl₃): δ 0.75-0.85 (2H, m), 1.20-1.31 (1H, m), 1.32 (6H, s), 1.96(2H, t, j=5.9 Hz), 3.01 (2H, t, j=5.9 Hz), 3.15-3.29 (2H, m), 7.00 (2H,s), 7.31 (1H, s).

Ethyl 3,7-dimethyl,6(RS),7(SR) methano-7-(4,4-dimethylthiochrman-6-yl),2(E),4(E)-heptadienoate (Compound 15) and Ethyl 3,7-dimethyl,6(RS),7(SR)methano-7-(4,4-dimethyl-thiochroman-6-yl),2(Z),4(E)-heptadienoate(Compound 16)

Employing the same general procedure as used for the preparation ofethyl 3,7-dimethyl,6(RS),7(SR)methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoate (Compound 2), but instead using 245 mgs (0.95mmol) of 3-methyl-2(RS),3(RS)-methano-314,4-dimethyl-thiochroman-6-yl!propan-1-ol (Compound Q),the starting material was converted to the isomeric title compounds inthe ratio of 4 (Compound 15) : 1 (Compound 16).

Compound 15

PMR (CDCl₃): δ 1.09 (1H, t, j=5.1 Hz), 1.17 (1H, dd, j=5.7, 8.2 Hz),1.25 (3H, s), 1.27 (3H, t, j=7.1 Hz), 1.32 (3H, s), 1.39 (3H, s),1.67-1.76 (1H, m), 1.92-1.98 (2H, m), 2.01 (3H, s), 2.98-3.04 (2H, m),4.14 (2H, q, j=7.1 Hz), 5.22 (1H, dd, j=10.0, 15.5 Hz), 5.64 (1H, s),6.20 (1H, d, j=15.5 Hz), 6.95 (1H, dd, j=1.8, 8.1 Hz), 7.01 (1H, d,j=8.1 Hz), 7.20 (1H, d, j=1.8 Hz).

Compound 16

PMR (CD₃ COCD₃) : δ 1.17-1.22 (2H, m), 1.22 (3H, t, j=7.1 Hz), 1.26 (3H,s), 1.30 (3H, s), 1.40 (3H, s), 1.67 (3H, s), 1.77-1.86 (1H, m),1.90-1.96 (2H, m), 2.97-3.03 (2H, m), 4.09 (2H, q, j=7.1 Hz), 5.27 (1H,dd, j=9.9, 15.9 Hz), 5.47 (1H, s), 6.95 (1H, d, j=8.2 Hz), 6.98 (1H, dd,j=1.7, S.2 Hz), 7.74 (1H, d, j=15.9 Hz).

3,7-Dimethyl,6(RS),7(SR) methano-7-(4,4-dimethylthiochroman-6-yl),2(E),4(E)-heptadienoic acid (Compound 17)

Employing the same general procedure as used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 100 mgs (0.28 mmol) of ethyl3,7-dimethyl, 6(RS),7(RS) methano-7-(4,4-dimethylthiochroman-6-yl),2(E),4(E)-heptadienoate (Compound 15) and LiOH in water (1M solution inwater, 0.4 ml) the title compound was obtained as a white solid.

PMR (CDCl₃): δ 1.10 (1H, t, j=4.9 Hz), 1.19 (1H, dd, j=4.9, 8.2 Hz),1.25 (3H, s), 1.32 (3H, s), 1.4 (3H, s), 1.69-1.79 (1H, m), 1.95 (2H, t,j=6.5 Hz), 2.01 (3H, s), 3.01 (2H, t, j=6.5 Hz), 5.27 (1H, dd, j=10.0,15.5 Hz), 5.66 (1H, s), 6.24 (1H, d, j=15.5 Hz), 6.95 (1H, dd, j=1.8,8.1 Hz), 7.01 (1H, d, j=8.1 Hz), 7.20 (1H, dd, j=1.8 Hz).

3,7-Dimethyl,6(RS),7(SR) methano-7-(4,4-dimethylthiochroman-6-yl),2(Z),4(E)-heptadienoic acid (Compound 18)

Employing the same general procedure as used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl), 2(E),4(E)-heptadienoicacid (Compound 2), but instead using 30 mgs (0.08 mmol) of ethyl3,7-dimethyl, 6(RS),7(RS) methano-7-(4,4-dimethyl-thiochrman-6-yl),2(Z),4(E)-heptadienoate (16) and LiOH in water (1M solution in water 0.5ml) the title compound was obtained as a white solid.

PMR (CDCl₃): δ 1.12 (1H, t, j=4.9 Hz), 1.22 (1H, dd, j=4.9, 8.1 Hz),1.28 (3H, s), 1.34 (3H, s), 1.41 (3H, s), 1.75 (3H, s), 1.82-1.92 (1H,m), 1.95-2.01 (2H, m), 3.03 (2H, t, j=5.9 Hz), 5.28 (1H, dd, j=10.1,15.7 Hz), 5.54 (1H, s), 6.97 (1H, dd,j=1.8, 8.0 Hz),7.03 (1H, d, j=8.0Hz), 7.24 (1H, d, j=1.8 Hz), 7.73 (1H, d, j=15.7 Hz.

Methyl 3-(4,4-dimethyl-chroman-6-yl)propiolate (Compound R)

Employing the same general procedure as used for the preparation ofethyl 3- 5,5,8,8,-tetramethyl-5,6, 7,8-tetrahydro-naphth-2-yl!propiolate(Compound A) but instead using 1.86 g (10 mmols) of4,4-dimethylchroman-6-yl!ethyne, 2 g (21.3 mmols) of methylchloroformateand 11 mmols of n-butyllithium the title compound was obtained as ayellow solid.

PMR (CDCl₃): δ 1.32 (6H, s), 1.82 (2H, t, j=5.6 Hz, 3.82 (3H, s), 4.22(2H, t, j=5.6 Hz), 6.75 (1H, d, j=8.6 Hz), 7.30 (1H, dd, j=2.0, 8.6 Hz),7.53 (1H, d, 2.0 Hz).

Methyl 3-(4,4-dimethyl-chroman-6-yl!but-2(Z)-enoate (Compound S)

Employing the same general procedure as for the preparation of ethyl 3-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphth-2-yl!but-2(Z)-enoate(Compound B) but instead using 1.4 g (5.7 mmols) of methyl3-(4,4-dimethyl-chroman-6-yl!propiolate (Compound R), 2.1 g (10.24mmols) of CuBr.DMS, 18 mmols of methyllithium in ether and maintainingthe temperature at -78° C. the title compound was obtained as acolorless oil.

PMR (CDCl₃): δ 1.34 (6H, s), 1.85 (2H, t, j=5.4 Hz), 2.18 (3H, s), 3.5s(3H, s), 4.20 (2H, t, j=5.4 Hz), 5.85 (1H, s), 6.76 (1H, d, j=8.5 Hz),7.00 (1H, dd, j=2.2 Hz, 8.5 Hz).

3- 4,4-Dimethyl-chroman-6-yl!but-2(Z)-en-1-ol (Compound T)

Employing the same general procedure used for the preparation of 3-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphth-2-yl!but-2(Z)-en-1-ol(Compound C) but instead using 270 mgs (1.04 mmols) of methyl 3-4,4-dimethyl-chroman-6-yl!but-2(Z)-enoate (Compound S) and 4 mmols ofdiisobutylaluminiumhydride the title compound was obtained as acolorless oil.

PMR (CDCl₃): δ 1.34 (6H, s), 1.85 (2H, t, j=5.4 Hz), 2.08 (3H, s), 4.12(2H, d, j=6.2 Hz), 4.20 (2H, d, j=5.4 Hz), 5.67 (1H, t, j=6.2 Hz), 6.75(1H, d, j=8.3 Hz), 6.92 (1H, dd, j=2.1, 8.3 Hz), 7.08 (1H, d, j=2.1 Hz).

3-Methyl-2(RS),3(SR)-methano-3 4,4-dimethyl-chroman-6-yl!propan-1-ol(Compound U)

Employing the same general procedure as used for the preparation of3-methyl-2(RS),3(SR)-methano-3 5,5,8-8-tetramethy1-5,6,7,S-tetrahydro-naphth-2-yl!propan-1-ol (CompoundD) but instead using 230 mgs (1 mmol) of 3-4,4-dimethyl-chroman-6-yl!but-2(Z)-en-1-ol (Compound T) 750 mgs (5mmols) of samarium, 130 mgs (0.5 mmol) of mercuricchloride and 1.35 g (5mmols) of diiodomethane the title compound was obtained as a colorlessoil.

PMR (CDCl₃): δ 0.74-0.83 (2H, m), 1.22-1.27 (1H, m), 1.33 (3H, s), 1.37(3H, s), 1.83 (2H, t, j=5.4 Hz), 3.12-3.34 (2H, m), 4.17 (2H, d, j=5.4Hz), 6.72 (1H, d, j=8.3 Hz), 7.02 (1H, dd, j=2.2, 8.3 Hz), 7.21 (1H, d,j=2.2 Hz).

Ethyl 3,7-dimethyl,6(RS),7(SR) methano-7-(4,4-dimethyl-chroman-6-yl),2(E),4(E) -heptadieonate (Compound 19) and ethyl3,7-dimethyl,6(RS),7(SR) methano-7-(4,4-dimethyl-chroman-6-yl),2(Z),4(E) -heptadienoate (Compound 20)

Employing the same general procedure as used for the preparation ofethyl 3,7-dimethyl,6(RS),7(SR)methano-7(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl),2(E),4(E)-heptadienoate (Compound 1) but instead using 110 mgs (0.5mmol) of 3-methyl-2(RS), 3(RS)-methano-34,4-diimethyl-chroman-6-yl!propan-1-ol (Compound U) isomeric titlecompounds were obtained in the ratio of 4 (Compound 19): 1 (Compound 20)

Compound 19

PMR (CDCl₃): δ 1.07 (1H, t, j=4.7 Hz), 1.15 (1H, dd, j=4.7, 8.2 Hz),1.26 (3H,), 1.26 (3H, t, j=7.1 Hz), 1.31 (3H, s), 1.38 (3H, s),1.65-1.74 (1H, m), 1.81 (2H, t, j=5.4 Hz), 1.99 (3H, s), 4.13 (2H, q, j=7.1 Hz), 4.17 (2H, t, j=5.4 Hz), 5.22 (1H, dd, j=9.9, 15.6 Hz), 5.63(1H, s), 6.19 (1H, d, j=15.6 Hz), 6.70 (1H, d, j=8.3 Hz), 6.96 (1H, dd,j=2.2, 8.3 Hz), 7.10 (1H, d, j=2.2 Hz).

Compound 20

PMR (CDCl₃): δ 1.07 (1H, t, j=4.7 Hz), 1.17 dd, j=4.7, 8.2 Hz), 1.25(3H, s), 1.29 (3H, t, j=7.1 Hz), 1.31 (3H, s), 1.37 (3H, s), 1.68 (3H,brs), 1.75-1.85 (3H, m), 4.12-4.21 (4H, m), 5.21 (1H, dd, j=8.9, 15.8Hz), 5.47 (1H, s), 6.70 (1H, d, j=8.3 Hz), 6.97 (1H, dd, j=2.2, 8.3 Hz),7.11 (1H, d, j=2.2 Hz), 7.72 (1H, d, j=15.8 Hz).

3,7-Dimethyl,6(RS),7(SR) methano-7-(4,4-dimethyl-chroman-6-yl),2(E),4(E)-heptadienoic acid (Compound 21)

Employing the same general procedure used for the preparation of3,7-dimethyl,6(RS),7(SR) methano-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphth-2-yl), 2(E),4(E) -heptadienoicacid (Compound 2) but instead using 21 mgs (0.06 mmol) of ethyl3,7-dimethyl, 6(RS),7(RS) methano-7-(4,4-dimethyl-chroman-6-yl),2(E),4(E)-heptadienoate (Compound 19) and LiOH in water (1M solution inwater 0.4 ml) gave the title compound as a white solid.

PMR (CDCl₃): δ 1.10 (1H, t, j=4.9 Hz), 1.18 (1H, dd, j=4.9, 8.1 Hz),1.26 (3H, s), 1.32 (3H, s), 1.40 (3H, s), 1.67-1.79 (1H, m), 1.82 (2H,t, j=5.8 Hz), 2.00 (3H, s), 4.17 (2H, t, j=5.8 Hz), 5.28 (1H, dd, j=9.9, 15.4 Hz), 5.65 (1H, s), 6.22 (1H, d, j=15.4 Hz), 6.72 (1H, d,j=8.3 Hz), 6.97 (1H, dd, j=2.1 Hz, 8.3 Hz), 7.10 (1H, d, j=2.1 Hz).

What is claimed is:
 1. A compound of the formula ##STR10## wherein R₂ ishydrogen or lower alkyl; R₃ is hydrogen or lower alkyl, andB ishydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈,CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O,--COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or tri-lower alkylsilyl, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons.
 2. A compound in accordance with claim 1 wherein R₂ ismethyl.
 3. A compound in accordance with claim 2 wherein B is COOH or apharmaceutically acceptable salt thereof, COOR₈ or CONR₉ R₁₀.
 4. Acompound in accordance with claim 3 where the phenyl group is attachedto the 2 position of the tetrahydronaphthalene nucleus.
 5. A compound inaccordance with claim 4 where the configuration about the double bondadjacent to the phenyl ring is trans.
 6. A compound in accordance withclaim 5 where the B group represents COOH, COOCH₃ or COOC₂ H₅, R₃ isattached to the 3 position of the tetrahydronaphthalene nucleus andconfiguration about the double bond adjacent to the B group is trans. 7.A compound in accordance with claim 6 where B is COOH.
 8. A compound inaccordance with claim 6 where B is COOC₂ H₅.
 9. A compound in accordancewith claim 5 where the B group represents COOH, COOCH₃ or COOC₂ H₅, R₃is attached to the 3 position of the tetrahydronaphthalene nucleus andconfiguration about the double bond adjacent to the B group is cis. 10.A compound in accordance with claim 9 where B is COOH.
 11. A compound ofthe formula ##STR11## where n is 1 or 2; R₁ and R₂ independently are H,lower alkyl or fluoroalkyl;R₃ is hydrogen, lower alkyl, Cl or Br; R₄ isH, lower alkyl, fiuoroalkyl or halogen, and B is hydrogen, COOH or apharmaceutically acceptable salt thereof, COOR₈, CONR₉ R₁₀, --CH₂ OH,CH₂ OR₁₁, CH₂ O COR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂,CR₇ OR₁₃ O, or tri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkylwhere the alkyl group has 1 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons.
 12. Acompound of the formula ##STR12## where R₄ is lower alkyl of 1 to 6carbons; B is COOH or COOR₈ where R₈ is lower alkyl of 1 to 6 carbons,andthe configuration about the cyclopropane ring is cis, and theconfiguration about the double bonds in the pentadienoic acid or esterchain attached to the cyclopropane ring is trans in each of said doublebonds, or a pharmaceutically acceptable salt of said compound.
 13. Acompound in accordance with claim 12 where B is COOH, and R₄ is methyl,or a pharmaceutically acceptable salt of said compound.
 14. A compoundin accordance with claim 12 where B is COOC₂ H₅, and R₄ is methyl.